Genomics Driving Diagnosis and Treatment of Inborn Errors of Immunity With Cancer Predisposition.

Inborn errors of immunity (IEI) are genetically and clinically heterogeneous disorders that, in addition to infection susceptibility and immune dysregulation, can have an enhanced cancer predisposition. The increasing availability of upfront next-generation sequencing diagnostics in immunology and oncology have uncovered substantial overlap of germline and somatic genetic conditions that can result in immunodeficiency and cancer. However, broad application of unbiased genetics in these neighboring disciplines still needs to be deployed, and joined therapeutic strategies guided by germline and somatic genetic risk factors are lacking. We illustrate the current difficulties encountered in clinical practice, summarize the historical development of pathophysiological concepts of cancer predisposition, and review select genetic, molecular, and cellular mechanisms of well-defined and illustrative disease entities such as DNA repair defects, combined immunodeficiencies with Epstein-Barr virus susceptibility, autoimmune lymphoproliferative syndromes, regulatory T-cell disorders, and defects in cell intrinsic immunity. We review genetic variants that, when present in the germline, cause IEI with cancer predisposition but, when arising as somatic variants, behave as oncogenes and cause specific cancer entities. We finally give examples of small molecular compounds that are developed and studied to target genetically defined cancers but might also proof useful to treat IEI.